The role of tolerogenic dendritic cells in the treatment of multiple sclerosis: From mechanism to clinical translation

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory demyelination and neurodegeneration within the central nervous system. Its pathogenesis is primarily driven by autoreactive T cells that infiltrate the blood-brain barrier and initiate immune-mediated damage against myelin antigens. Although current disease-modifying therapy can delay disease progression, they largely rely on non-specific immunosuppression and are associated with increased risks of infection and malignancy, while failing to achieve durable immune tolerance or functional cure. Therefore, the development of antigen-specific immunotherapies capable of restoring immune homeostasis has become a critical unmet need. Tolerogenic dendritic cells (tolDCs) have emerged as a promising strategy for inducing antigen-specific immune tolerance in MS. As key regulators bridging innate and adaptive immunity, dendritic cells exhibit functional plasticity, enabling them to either promote inflammatory responses or induce immune tolerance depending on environmental cues. tolDCs are characterized by low expression of co-stimulatory molecules, high expression of inhibitory receptors, and enhanced secretion of anti-inflammatory cytokines such as interleukin-10 <?A3B2 pi129?>and transforming growth factor-β. These cells suppress autoreactive T cell activation, promote regulatory T cells and regulatory B cells differentiation, and reshape immune responses toward a tolerogenic state. This review systematically summarizes the biological features, induction strategies, and molecular mechanisms underlying tolDC-mediated immune tolerance. We highlight multi-layered regulatory pathways, including immunosuppressive signaling (e.g., programmed death-1/programmed death ligand-1 <?A3B2 pi129?>and cytotoxic T lymphocyte antigen-4), metabolic reprogramming, transcriptional and epigenetic networks, and apoptosis-mediated deletion of pathogenic T cells. In addition, we provide an overview of current approaches for generating tolDCs, including pharmacological modulation, cytokine conditioning, genetic engineering, and in vivo targeting strategies using nanoparticles or receptor-specific delivery systems. Evidence from experimental autoimmune encephalomyelitis models and early-phase clinical trials demonstrates that tolDC-based therapies are safe, feasible, and capable of inducing antigen-specific immune regulation. Despite these advances, several challenges remain for clinical translation, including the heterogeneity and stability of tolDCs, lack of standardized manufacturing protocols, patient-specific antigen selection, and the need for robust immune monitoring biomarkers. Future directions should focus on integrating multi-omics technologies, precision antigen identification, and bioengineering approaches to enhance the specificity, stability, and scalability of tolDC-based therapies. Ultimately, tolDCs represent a transformative platform shifting from broad immunosuppression toward precise immune reprogramming, offering new therapeutic opportunities for MS and other autoimmune diseases. <alternatives id="alt2"> </alternatives>